Thienopyrimidine derivative and use thereof in medicine

Abstract

The present invention relates to a thienopyrimidine derivative and use thereof in medicine, and also to a pharmaceutical composition containing the compound. The compound or pharmaceutical composition is used for inhibiting acetyl-CoA carboxylase (ACC). The present invention also relates to a method of preparing such compound and pharmaceutical composition, as well as their use in the treatment or prevention of diseases regulated by acetyl-CoA carboxylase in mammals, especially in humans.

What is claimed is: 
     
       1. A compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         Het is —C(═O)NR a R b , —C(═NR)NR a R b , —NH—C(═NR)NR a R b , 3-10 membered heterocyclyl or 5-10 membered heteroaryl; wherein each of 3-10 membered heterocyclyl and 5-10 membered heteroaryl is independently and optionally substituted with H, oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, carboxy and —C(═O)NH 2 ; 
         R 1  is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-6  alkyl, C 1-6  alkoxy or C 1-6  haloalkyl; 
         R 2  is —OR or —NR a R b ; 
         each of R 3  and R 4  is independently H, C 1-6  alkyl, C 1-6  hydroxyalkyl or C 1-6  haloalkyl; 
         L is —O—, —O-methylene-, —O-ethylene-, —S— or —NH—; 
         R 5  is C 6-10  aryl or 5-10 membered heteroaryl, wherein each of C 6-10  aryl and 5-10 membered heteroaryl is independently and optionally substituted with 1, 2 or 3 R 6 ; wherein R 6  is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 1-6  cyanoalkyl or C 1-6  hydroxyalkyl; and 
         W is fused cyclyl, bridged cyclyl or spiro cyclyl, wherein fused cyclyl, bridged cyclyl or spiro cyclyl is saturated or partially unsaturated 6-12 membered cyclyl containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; and wherein W is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, —C(═O)OR, —C(═O)NR a R b , —C(═NR)NR a R b , —NH—C(═NR)NR a R b , —SO 2 R, —SO 2 NR a R b , C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 1-6  alkylamino, C 1-6  haloalkyl, C 1-6  cyanoalkyl and C 1-6  hydroxyalkyl; 
         wherein each R, R a  and R b  is independently H, C 1-6  alkyl, C 1-6  haloalkyl or C 3-8  cycloalkyl; or R a  and R b , together with the N atom to which they are attached, form 3-10 membered heterocyclyl; and wherein 3-10 membered heterocyclyl is optionally substituted with oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-6  alkyl, C 1-6  alkoxy and C 1-6  haloalkyl. 
       
     
     
       2. The compound of  claim 1 , wherein Het is 5-6 membered heterocyclyl or 5-6 membered heteroaryl; and wherein each of 5-6 membered heterocyclyl and 5-6 membered heteroaryl is independently and optionally substituted with H, oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, carboxy and —C(═O)NH 2 . 
     
     
       3. The compound of  claim 1 , wherein Het is pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolidyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, wherein each of pyrrolidyl, tetrahydrofuryl, imidazolidinyl, pyrazolidyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl is independently and optionally substituted with H, oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, carboxy and —C(═O)NH 2 . 
     
     
       4. The compound of  claim 1 , wherein R 1  is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3  alkyl, C 1-3  alkoxy or C 1-3  haloalkyl; and
 R 2  is —OR or —NR a R b ; 
 wherein each R, R a  and R b  is independently H, C 1-3  alkyl, C 1-3  haloalkyl or C 3-6  cycloalkyl; or R a  and R b , together with the N atom to which they are attached, form 4-6 membered heterocyclyl; and wherein 4-6 membered heterocyclyl is optionally substituted with oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3  alkyl, C 1-3  alkoxy and C 1-3  haloalkyl; and 
 each of R 3  and R 4  is independently H, C 1-3  alkyl, C 1-3  hydroxyalkyl or C 1-3  haloalkyl. 
 
     
     
       5. The compound of  claim 1 , wherein R 1  is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl or trifluoroethyl; and
 R 2  is —OR or —NR a R b ; 
 wherein each R, R a  and R b  is independently H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; 
 or R a  and R b , together with the N atom to which they are attached, form heterocyclyl selected from heterocyclyl groups represented by formulae (I-a) to (I-k): 
 
       
         
           
           
               
               
           
         
         wherein the heterocyclyl groups represented by formulae (I-a) to (I-k) are optionally substituted with oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl or trifluoroethyl; and 
         each of R 3  and R 4  is independently H, methyl, ethyl, n-propyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or 2-fluoroethyl. 
       
     
     
       6. The compound of  claim 1 , wherein R 5  is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl or 5-6 membered heteroaryl, wherein each of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and 5-6 membered heteroaryl is independently and optionally substituted with 1, 2 or 3 R 6 ; and wherein R 6  is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  haloalkoxy, C 1-3  cyanoalkyl or C 1-3  hydroxyalkyl. 
     
     
       7. The compound of  claim 1 , wherein R 5  is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl or pyridazinyl, wherein each of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyranyl and pyridazinyl is independently and optionally substituted with 1, 2 or 3 R 6 ; and wherein R 6  is H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, hydroxymethyl, hydroxyethyl, cyanomethyl or cyanoethyl. 
     
     
       8. The compound of  claim 1 , wherein W has one of the following structures: 
       
         
           
           
               
               
           
         
         each of X 1 , X 2  and X 3  is independently a bond, —CH 2 —, —O—, —S— or —NH—; 
         Y is CH or N; 
         each r, s, t and n is independently 0, 1, 2, or 3; and 
         each W is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, —C(═O)OH, —C(═O)NH 2 , —C(═NH)NH 2 , —NH—C(═NH)NH 2 , —SO 2 CH 3 , —SO 2 C 2 H 5 , C 1-3  alkyl, C 3-6  cycloalkyl, C 1-3  alkoxy, C 1-3  haloalkoxy, C 1-3  alkylamino, C 1-3  haloalkyl, C 1-3  cyanoalkyl and C 1-3  hydroxyalkyl. 
       
     
     
       9. The compound of  claim 1 , wherein W has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each W is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from oxo (═O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, —C(═O)OH, —C(═O)NH 2 , —C(═NH)NH 2 , —NH—C(═NH)NH 2 , —SO 2 CH 3 , —SO 2 C 2 H 5 , methyl, ethyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, methylamino, cyanomethyl and hydroxymethyl. 
       
     
     
       10. The compound of  claim 1  having one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer, a geometric isomer, a tautomer, an N oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. 
     
     
       11. A pharmaceutical composition comprising the compound of  claim 1 . 
     
     
       12. The pharmaceutical composition of  claim 11  further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. 
     
     
       13. A method of treating or lessening a disorder or disease regulated by acetyl-CoA carboxylase in a patient comprising administering to the patient a therapeutically effective amount of the compound of  claim 1 , wherein the disorder or disease is obesity, metabolic syndrome, diabetes, non-alcoholic steatohepatitis, breast cancer, colorectal cancer or prostate cancer. 
     
     
       14. A method of treating or lessening a disorder or disease regulated by acetyl-CoA carboxylase in a patient comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of  claim 11 , wherein the disorder or disease is obesity, metabolic syndrome, diabetes, non-alcoholic steatohepatitis, breast cancer, colorectal cancer or prostate cancer.